NM_001370466.1:c.1196G>A
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_StrongBS2
The NM_001370466.1(NOD2):c.1196G>A(p.Arg399His) variant causes a missense change. The variant allele was found at a frequency of 0.0000564 in 1,614,058 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R399C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001370466.1 missense
Scores
Clinical Significance
Conservation
Publications
- Blau syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, G2P, Illumina, Labcorp Genetics (formerly Invitae)
- inflammatory bowel disease 1Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
Genome browser will be placed here
ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NOD2 | NM_001370466.1 | c.1196G>A | p.Arg399His | missense_variant | Exon 4 of 12 | ENST00000647318.2 | NP_001357395.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152194Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000877 AC: 22AN: 250964 AF XY: 0.0000589 show subpopulations
GnomAD4 exome AF: 0.0000581 AC: 85AN: 1461746Hom.: 1 Cov.: 39 AF XY: 0.0000468 AC XY: 34AN XY: 727180 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74474 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29697845, 32085886, 34440800, 32677123) -
Regional enteritis;C5201146:Blau syndrome Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 426 of the NOD2 protein (p.Arg426His). This variant is present in population databases (rs562225614, gnomAD 0.02%). This missense change has been observed in individual(s) with early-onset inflammatory bowel disease (PMID: 29697845). ClinVar contains an entry for this variant (Variation ID: 531600). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOD2 protein function. Experimental studies have shown that this missense change affects NOD2 function (PMID: 29697845). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at